Pre-B-cell leukemias in Btk/Slp65-deficient mice arise independently of ongoing V(D)J recombination activity
| Autor: | Gemma M. Dingjan, A B de Haan, Rudolf W. Hendriks, M.J.W. De Bruijn, Van B. T. Ta |
|---|---|
| Přispěvatelé: | Pulmonary Medicine, Immunology |
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Immunoglobulin Variable Region Recombination-activating gene Mice RAG2 Precursor B-Cell Lymphoblastic Leukemia-Lymphoma hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Animals Bruton's tyrosine kinase Adaptor Proteins Signal Transducing Homeodomain Proteins Mice Knockout Recombination Genetic Recombinase activity biology V(D)J recombination breakpoint cluster region Receptor editing Hematology Protein-Tyrosine Kinases Virology Molecular biology Mice Inbred C57BL Oncology Pre-B Cell Receptors biology.protein Immunoglobulin Joining Region Immunoglobulin Light Chains Tyrosine kinase |
| Zdroj: | Leukemia, 25(1), 48-56. Nature Publishing Group |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | The adapter protein Slp65 and Bruton's tyrosine kinase (Btk) are key components of the precursor-B (pre-B) cell receptor (pre-BCR) signaling pathway. Slp65-deficient mice spontaneously develop pre-B-cell leukemia, expressing high levels of the pre-BCR on their cell surface. As leukemic Slp65-deficient pre-B cells express the recombination activating genes (Rag) 1 and Rag2, and manifest ongoing immunoglobulin (Ig) light-chain rearrangement, it has been hypothesized that deregulated recombinase activity contributes to malignant transformation. In this report, we investigated whether Rag-induced DNA damage is involved in oncogenic transformation of Slp65-deficient B cells. We employed Btk/Slp65 double-deficient mice carrying an autoreactive 3-83 mu delta BCR transgene. When developing B cells in their bone marrow express this BCR, the V(D)J recombination machinery will be activated, allowing for secondary Ig light-chain gene rearrangements to occur. This phenomenon, called receptor editing, will rescue autoreactive B cells from apoptosis. We observed that 3-83 mu delta transgenic Btk/Slp65 double-deficient mice developed B-cell leukemias expressing both the 3-83 mu delta BCR and the pre-BCR components lambda 5/VpreB. Importantly, such leukemias were found at similar frequencies in mice concomitantly deficient for Rag1 or the non-homologous end-joining factor DNA-PKcs. We therefore conclude that malignant transformation of Btk/Slp65 double-deficient pre-B cells is independent of deregulated V(D) J recombination activity. Leukemia (2011) 25, 48-56; doi: 10.1038/leu.2010.246; published online 29 October 2010 |
| Databáze: | OpenAIRE |
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